Heart valve replacement may be indicated when there is a narrowing of the native heart valve, commonly referred to as stenosis, or when the native valve leaks or regurgitates, such as when the leaflets are calcified. In one therapeutic solution, the native valve may be excised and replaced with either a biologic or a mechanical valve.
Tissue-type or “bioprosthetic” valves have flexible leaflets supported by a base structure that project into the flow stream and function much like those of a natural human heart valve by coapting against each other to ensure one-way blood flow. In tissue-type valves, a whole xenograft valve (e.g., porcine) or a plurality of xenograft leaflets (e.g., bovine pericardium) typically provide fluid occluding surfaces. Synthetic leaflets have also been proposed. Two or more flexible leaflets mount within a peripheral support structure, for example as seen in the CARPENTIER-EDWARDS Porcine Heart Valve and PERIMOUNT Pericardial Heart Valve available from Edwards Lifesciences of Irvine, Calif.
Implantable biological tissues can be formed of human tissues preserved by freezing (i.e., cryopreserving) the homograft tissues, or of animal tissues preserved by chemically fixing (i.e., tanning) the xenograft tissues. The type of biological tissues used as bioprostheses include cardiac valves, blood vessels, skin, dura mater, pericardium, small intestinal submucosa (“SIS tissue”), ligaments and tendons. These biological tissues typically contain connective tissue proteins (i.e., collagen and elastin) that act as the supportive framework of the tissue. The pliability or rigidity of each biological tissue is largely determined by the relative amounts of collagen and elastin present within the tissue and/or by the physical structure and configuration of its connective tissue framework. Collagen is the most abundant connective tissue protein present in most tissues. Each collagen molecule is made up of three (3) polypeptide chains intertwined in a coiled helical configuration.
The techniques used for chemical fixation of biological tissues typically involve the exposure of the biological tissue to one or more chemical fixatives (i.e., tanning agents) that form cross-linkages between the polypeptide chains within a given collagen molecule (i.e., intramolecular crosslinkages), or between adjacent collagen molecules (i.e., intermolecular crosslinkages). Examples of chemical fixative agents that have been utilized to cross-link collagenous biological tissues include: formaldehyde, glutaraldehyde, dialdehyde starch, hexamethylene diisocyanate and certain polyepoxy compounds.
One problem associated with the implantation of many bioprosthetic materials is that the connective tissue proteins (i.e., collagen and elastin) within these materials can become calcified following implantation within the body. Such calcification can result in undesirable stiffening or degradation of the bioprosthesis.
Of the various chemical fixatives available, glutaraldehyde (also referred to as simply “glut”) has been the most widely used since the discovery of its antiimmunological and antidegenerative effects by Dr. Alain Carpentier in 1968. See Carpentier, A., J. Thorac. Cardiovascular Surgery, 58: 467-69 (1969). In addition, glutaraldehyde is one of the most efficient sterilization agents. Glutaraldehyde is therefore used as the fixative and the sterilant for many commercially available bioprosthetic products, such as in the bioprosthetic heart valve available from Edwards Lifesciences of Irvine, Calif.
Various techniques have been proposed for mitigating the in vivo calcification of glutaraldehyde-fixed bioprostheses or for otherwise improving the glutaraldehyde fixation process. Included among these are the methods described in U.S. Pat. No. 4,729,139 (Nashef); U.S. Pat. No. 4,885,005 (Nashef et al.); U.S. Pat. No. 4,648,881 (Carpentier et al.); U.S. Pat. No. 5,002,566 (Carpentier); EP 103947 (Pollock et al.), and U.S. Pat. No. 5,215,541 (Nashef et al.). The techniques proposed in U.S. Pat. No. 5,862,806 (Cheung) include dehydration of glutaraldehyde treated tissues prior to the application of a chemical reducing agent such as sodium cyanoborohydride or sodium borohydride. The calcification mitigation techniques found in U.S. Pat. No. 6,471,723 involve addition of a variety of amine functions in an effort to detoxify the aldehyde groups in glutaraldehyde-fixed tissue. These chemicals are not permanently attached to the tissue and will diffuse out of the tissue over time. The use of reducing agents in conjunction with ethanol treatment is shown in Connolly, J., J. Heart Valve Disease, 13: 487-493 (2004) as being beneficial for mitigating calcification. This publication indicates that the use of reducing agents does not adversely affect the morphology or tissue shrinkage temperature of the tissue.
Recently a new technique of calcium mitigation by elevated temperature fixation of the tissue in glutaraldehyde has been developed and was described in U.S. Pat. No. 6,561,970 (Carpentier et al.), and in combination with relative tissue/fluid movement in U.S. Pat. No. 5,931,969 (Carpentier et al.). Another technique involving adjusting the pH of a glutaraldehyde fixation solution is disclosed in U.S. Pat. No. 6,878,168 (Carpentier et al.). A commercial embodiment, the Edwards Lifesciences XenoLogiX™ Tissue Treatment, eliminates up to 98% of phospholipids in an attempt to reduce calcium binding sites. In the Carpentier-Edwards ThermaFix™ Advanced Heart Valve Tissue Process also from Edwards Lifesciences, both thermal and chemical treatments are used to remove unstable glutaraldehyde molecules which reduces calcium binding sites, resulting in a marked reduction in calcium uptake versus glutaraldehyde-only controls.
Although some of these known techniques have proven to be somewhat effective, there remains a need for further improvements to lessen the propensity for long-term post-implantation calcification of fixed bioprosthetic tissues for use in implants, in particular heart valves. The prior art does not address the changes within the tissue that can occur as a result of the service (implant) environment.